6-(2,5-dioxo-4-phenyl-n-substituted-4-imidazolinecarboxamido)penicillanic acids

ABSTRACT

Novel 6-(2,5-dioxo-4-phenyl-N-substituted-4imidazolidinecarboxamido)penicillanic acids and intermediates are described which are useful as antibacterial agents.

United States Patent 1 Sellstedt et al.

541 6-(2,5-DIOX0-4-PHENYL-N- SUBSTITUTED-4-IMIDAZOLINECAR-BOXAMIDO)PENICILLANIC ACIDS Inventors: John H. Sellstedt, King ofPrussia;

Stanley C. Bell, Penn Valley, both of Pa.

Appl. No.: 174,980

U.S. Cl ..260/239.l, 424/271 Int. Cl. ..C07d 99/16 Field of Search..260/239.1

[ 1 Jan. 30, 1973 [56] References Cited UNITED STATES PATENTS 3,471,47510/1969 Clark et a1 ..260/239.1 3,538,083 11/1970 Grant et al...260/239.1 3,621,01 1

11/1971 Russell ct al. ..260/239.1

Primary Examiner-Nicholas S. Rizzo AuorneyVito Victor Bellino et al.

[57] ABSTRACT Novel 6-(2,5-dioxo-4-phenyl-N-substituted-4-imidazolidinecarboxamido)penicillanic acids and intermediates aredescribed which are useful as antibacterial agents.

4 Claims, No Drawings 6-(2,5-DlOXO-4-PHENYL-N-SUBSTlTUTED-t-[MlDAZOLlNECARBOXAMIDOWENICILLANIC wherein R and/or R is a memberselected from the class consisting of hydrogen, (lower)alkyl andaryl(lower)alkyl. R is a member selected from the group consisting ofhydrogen, (lower)-alkyl, (lower)alkoxy, halo, nitro, hydroxy, anddiloweralkyl sulfamyl. R is preferably hydrogen.

Also contemplated within the scope of this invention are novelpenicillin intermediates represented by the formula:

o V Ji I S OH: N I CONH 0- L l OzH R2 II wherein R has the same meaningas in formula I. These compounds are useful as intermediates forpreparing compounds of formula I wherein each of R and R, is hydrogen.The compounds of formula II also have antibacterial activity.

The term lower alkyl as employed herein includes both straight andbranch chain radicals of C through C-, carbons as exemplified by methyl,ethyl, propyl, isopropyl, n-butyl, l,l-dimethyl butyl, hexyl, etc. Theterm aryl(lower)alkyl" means monocyclic and bicyclic carbocyclic aryllower alkyl radicals exemplified by benzyl, B-phenylethyl,a-phenylpropyl, aphenyl-ethyl, anaphthylethyl. The term halo meanschlorine, bromine, fluorine, and iodine. The term lower alkoxy meansboth straight and branch chain radicals of C through C, carbons asexemplified by methoxy, ethoxy, butoxy, isobutoxy, pentoxy, etc.

The novel products of this invention form salts which are also part ofthe invention. Non-toxic pharmaceutically acceptable salts of the acidiccarboxylic acid group of the penicillin compounds include potassium,calcium, sodium, ammonium, procaine, dibenzylamine,N,N'-dibenzylethylenediamine, N-ethylpiperidine, etc.

The novel penicillins of this invention are prepared according to thefollowing reaction:

III IV wherein R, has the same meaning as in formula I and R and R aretrimethylsilyl, (lower)alkyl and ara(lower)alkyl.

The compound of formula III may be prepared by the procedure describedin Example I. The compound of formula IV wherein R and R, istrimethylsilyl may be prepared in the manner described in Example 2. Thecompounds of formula W wherein each of R and R, is other thantrimethylsilyl may be prepared in accordance with procedures well-knownin the art such as that described by Henze et al., J. Am. Chem. Soc. 64,522 (1942) and Henze et al., J. Am. Chem. Soc. 76, 4152 (1954).

In carrying out the process of the present invention the use of water asshown in the above reaction sequence is necessary only where R and R aretrimethylsilyl in order to hydrolyze this group and obtain a penicillincompound of formula I wherein each of R and R is hydrogen. In otherwords, in carrying out the process of the present invention, each of thetwo ring nitrogen atoms of the imidazolidine compounds of formula IVshould carry a substituent so that they will remain non-reactive duringthe formation of the compounds of formula I.

The novel compounds of the present invention are useful as therapeuticagents in poultry and mammals in the treatment of infectious diseasescaused by grampositive and gramnegative bacteria upon parenteral or oraladministration. They are also useful in in vitro applications, such asdisinfecting compositions.

The following examples serve to illustrate the invention.

EXAMPLE 1 o-isocyanatopenicillanic acid, trimethylsilyl ester In a 5liter three-necked flask equipped with stirrer, dropping-funnel, P O-tube and gas inlet tube, through which nitrogen is admitted, 2 litersof toluene and 150.5 g. (697 mmoles) of 6-aminopenicillanic acid areplaced. 220 ml. (I579 mmoles) of triethylamine are added and over aperiod of about 20 min. 250 ml. (approximately 1,980 mmoles) oftrimethylchlorosilane are added dropwise. Stirring is continued at roomtemperature for 2.5 hours after completion of the addition. Another oneliter of toluene is added and the temperature is brought to 60C. Next,ml. (646 mmoles) of triethylamine are added. Then, ll2 mi. (about l.8mole) of liquid phosgene is added while the temperature of the reactionmixture is kept below -40C. Stirring is continued for 3 hours at -40C.,at this temperature the precipitate formed is filtered off undernitrogen and washed with 500 ml. of toluene. From the combined filtrateand washing the greater part of the phosgene is removed by evaporationat 40C. The temperature is then slowly brought to -20C., under reducedpressure. The remaining traces of phosgene, together withtrimethylchlorosilane and triethylamine are removed while thetemperature is allowed to slowly rise to +25C., simultaneously most ofthe toluene is Formula -I removed. During the evaporation procedurepressure is maintained between 0.5 and 1.5 mm. Hg. The final volume ofthe solution is 750 ml. containing 263 mg./ml. of the trimethylsilylester of 6-isocyanato penicillanic acid. (yield: 80 percent).

Twenty-five ml. of this solution of the isocyanate in toluene isconcentrated under reduced pressure with exclusion of moisture, to avolume of about 10 ml. spontaneous crystallization occurs. 3 ml. ofanhydrous toluene are added and the crystalline product is filtered withsuction under nitrogen and washed twice with toluene. The crystals arefreed from traces of toluene and stored in a nitrogen atmosphere. Theyield is about 4 g. of trimethylsilyl ester of 6-isocyanato penicillanicacid having melting point 85 88C. [41],, 163.3C. in toluene. Themolecular weight according to mass spectroscopy is 3 14.

Analysis: (C, H and N) for C,,H,,,N,O,SSi:

calcd (percent): C, 45.86;H, 5.73; N, 8.92 found: (percent): C, 45.92;H, 5.78; N, 8.87

EXAMPLE 2 S-phenyl'l ,3bistrimethylsilylhydantoin Trimethychlorosilane(21 g., 0.191 mol) is dripped intov a mixture of S-phenyl hydantoin (14g., 0.0795 mol) and triethylamine (16.15 g., 0.16 mol) in 200 ml. ofbenzene, and the mixture is refluxed under nitrogen for 2 hr. and keptover night at room temperature. The mixture is filtered under anhydrousconditions and the cake is washed with 100 ml. of boiling benzene. Thebenzene is distilled off and the residue distilled at 126-l35/0.l mm.giving 25 g. of a water white oil which is the above titled product.

Analysis: calcd for C, H N O Si:

(percent) C, 56.20; H, 7.52; N, 8.73 found: C, 55.53; H, 7.36; N, 8.59

EXAMPLE 3 6-(2,5dioxo-4-phenyl-4-imidazolidineca'rboxamido)penicillanicacid potassium salt A solution of 6.23 g. mmole.) of 5-phenyl-N,N-bistrimethylsilyl hydantoin (Example 2) in 20 ml. of dry toluene iscooled to 40C. A solution of 12.5 ml. of1.6 N-butyllithium in hexane,20ml. of hexane, and 3 ml. of N,N,N',Ntetramethylethylenediamine isdripped into the hydantoin solution at 40C., and the solution stirredfor 2 hrs. A solution 6.3 g., (20 mmol.) of 6-isocyanatopenicillanicacid,-trimethylsilyl ester in 20 ml. of toluene is added dropwise over 5min. and the resulting solutionis stirred at 40C. for 1 hr. 3 m1. oftrimethylchlorosilane is added and the solution. is allowed to warm toroom temperature. This solution contains the compound6-(2,5-dioxo-l,3-bis-(trimethylsilyl)-4-phenyl-4-imidazolidinecarboxamido)penicillanic acid trimethylsilyl ester. The solution is thenpoured into an ether-ice water mixture, filtered and the water isextracted, once more with ether. The ether is washed with cold, dilutehydrochloric acid, brine and dried with magnesium sulfate. 9 ml. of 2 Mpotassium 2-ethylhexanoate in l-butanol is added to the ether to give awhite salt which is the above titled compound: NMR(D,O) 1.45-1.70 (Broads, 6, CH CCH 4.31 (s, 1, CHCO K), 5.40-5.75 (Broad m, 2, N CHCH), 7.47(Broad s, 5, aromatic).

EXAMPLE 4 Following the procedure of Example 3, the following compoundsmay be prepared by reacting 6-isocyanatopenicillanic acid,trimethylsilyl ester with a substituted phenyl hydantoin:

Hydantoin Derivative Productphenyl-4-imidazolidineearboxamido)penicillanic acid5-phenyl-N,N'-dibenzyl hydantoin 6-( l ,3-dibenzyl-2,5-dioxo-4-phenyl-4-imidazolidinecarboxamido)penicillanic acid5-(p-chlorophenyl)-N,N-

bistrimethylsilyl hydantoin 6-[4-(p-chlorophenyl)-2,5-dioxo-4-imidazolidinecarboxainido lpenicillanic acid 5-(p-methoxyphenyl)-N,N'-

dimethyl hydantoin 6-[4(p-methoxyphcnyl)-l ,3-

dimethyl-2,5-dioxo-4- 1 imidazolidinecarboxamido] enicillanic acid5-(o-nitrophenyl)-N,N'-

bistrimethyl hydantoin 6-[4-(O-nitrophenyl)-l,3-

dimethyl-2,5-dioxo-4- imidazolidinecarboxamidflp enicillanic acid5-(p-trimethylsilyloxy)-N,N'-

bistrimethyl hydantoin 6-[4-(p-hydroxyphehyU-l ,3-

dimethyl-2,5-dioxo-4- imidazolidinecarboxamidolp enicillanic acid Thecompounds of formula I of this invention have been found to possessantibacterial activity. Antibacterial screening is carried out by anagar serial dilution technique. Distilled water is used as a vehicle.The stock solution is prepared at 10,000 ugJml. of substance in thevehicle. Two-fold' dilutions are made with sterile water. 1 ml.quantities of each dilution are incorporated into 9 ml. seed agar insterile petrie dishes. The hardened surface is inoculated with testorganisms and incubated 18 hours at 35C. The end point is reported as aminimal inhibitory concentration (MIC) expressed in ugJmL; the leastamount of test substance that will completely inhibit the test organism.The compound of Example 3 when tested against Staphylococcus aureus6538i Staphylococcusaureus Smith, and Bacillus subtil- [as produced aMIC value in each case of 1.95 ugJml.

The compounds of this invention may be used in cleaning or disinfectingcompositions (e.g., dairy barns) at a concentration of about b 0.1 to 1percent by weight of such compositions dissolved or suspended in asuitable inert carrier for application by washing or spraying.

What is claimed is: V

l. A member selected from the group consisting of the compounds havingthe formula:

wherein R and R are members selected from the class consisting ofhydrogen, (lower)alkyl, aryl(lower)alkyl and trimethylsilyl, the wordaryl-meaning phenyl or naphthyl; R is a member selected from the classconl,3-bis-(trimethylsilyl)-4-phenyl-4-imidazolidinecarboxamido)penicillanicacid trimethylsilyl ester.

4. The compound of claim 1 which is: 6-(2,5-dioxo-4-phenyl-4-imidazolidinecarboxamido) penicillanic acid.

1. A member selected from the group consisting of the compounds havingthe formula:
 2. A compound according to claim 2 wherein R2 is hydrogen.3. The compound of claim 1 which is:6-(2,5-dioxo-1,3-bis-(trimethylsilyl)-4-phenyl-4-imidazolidinecarboxamido)penicillanic acid trimethylsilyl ester.